Recent observations indicate that the induction of certain antibody responses may aide the clearance of self-antigens associated with cell debris, aiding in the sequestration and disposal of "cellular garbage". We will test the mechanistic hypothesis that the Toll-like receptor (TLR) system is involved in the early in vivo clonal selection of B-1 cells responsible for natural auto-immunity, which may provide a protective function to ameliorate or even prevent the progression of autoimmune pathology. In part, our hypothesis is based on observations recently made in hyperlipidemic atherosclerosis-prone mice, in which the induction of protective B-1 cell derived anti-phospholipid antibody responses halted the progression of vascular disease. However, this effect has not previously been examined in murine models of autoimmunity. In Specific Aim 1, we will examine the interplay between the innate and adaptive immune systems by examining the mechanisms responsible for the emergence of these protective responses. In these studies, we will study MyD88 knockout mice, as well as TLR2, 4 and 9 knockout mice, to evaluate the role of these receptor molecules in the induction of protective natural autoimmune antibody responses. In Specific Aim 2, we will induce high in vivo levels of protective B- 1 cell derived IgM T 15 antibody in a well-established murine lupus model, NZB/W F1 mice, and assess whether these interventions can slow or even prevent the progression of pathologic autoantibody responses and lupus organ damage.